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Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: a Systematic Review

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Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: a Systematic Review antioxidants Review Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review Chisato Fujimoto 1,2,* and Tatsuya Yamasoba 1 1 Department of Otolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; [email protected] 2 Department of Otolaryngology, Tokyo Teishin Hospital, 2-14-23, Fujimi, Chiyoda-ku, Tokyo 102-8798, Japan * Correspondence: [email protected]; Tel.: +81-3-5800-8665; Fax: +81-3-3814-9486 Received: 14 April 2019; Accepted: 23 April 2019; Published: 24 April 2019 Abstract: Mitochondrial dysfunction is associated with the etiologies of sensorineural hearing loss, such as age-related hearing loss, noise- and ototoxic drug-induced hearing loss, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) and ROS-induced oxidative stress is involved in cochlear damage. Moreover, the release of ROS causes further damage to mitochondrial components. Antioxidants are thought to counteract the deleterious effects of ROS and thus, may be effective for the treatment of oxidative stress-related diseases. The administration of mitochondria-targeted antioxidants is one of the drug delivery systems targeted to mitochondria. Mitochondria-targeted antioxidants are expected to help in the prevention and/or treatment of diseases associated with mitochondrial dysfunction. Of the various mitochondria-targeted antioxidants, the protective effects of MitoQ and SkQR1 against ototoxicity have been previously evaluated in animal models and/or mouse auditory cell lines. MitoQ protects against both gentamicin- and cisplatin-induced ototoxicity. SkQR1 also provides auditory protective effects against gentamicin-induced ototoxicity. On the other hand, decreasing effect of MitoQ on gentamicin-induced cell apoptosis in auditory cell lines has been controversial. No clinical studies have been reported for otoprotection using mitochondrial-targeted antioxidants. High-quality clinical trials are required to reveal the therapeutic effect of mitochondria-targeted antioxidants in terms of otoprotection in patients. Keywords: antioxidants; hearing loss; mitochondria; reactive oxygen species 1. Introduction Many studies have been carried out under the assumption that mitochondrial dysfunction is an important pathological condition leading to hearing loss. Sensorineural hearing loss (SNHL), a type of hearing loss, occurs due to damage to the hair cells (HCs) in the cochlea and/or damage to the auditory neural pathway. Mitochondrial dysfunction is associated with the etiologies of SNHL, such as age-related hearing loss (ARHL), noise-induced hearing loss (NIHL) and ototoxic drugs, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) [1,2]. ROS-induced oxidative stress and collapse of the redox state are involved in cochlear damage [3,4]. Moreover, the release of ROS causes further damage to mitochondrial components, such as mtDNA, mitochondrial membranes and respiratory chain proteins, as well as nuclear DNA associated with mitochondrial function [5]. Antioxidants are thought to counteract the deleterious effects of ROS and may be effective in the treatment of oxidative stress-related diseases, including part of SNHL. Recently, novel treatments based on antioxidant compounds that specifically target mitochondria have been developed for diseases associated with mitochondrial dysfunction. Mitochondria-targeted antioxidants are superior Antioxidants 2019, 8, 109; doi:10.3390/antiox8040109 www.mdpi.com/journal/antioxidants Antioxidants 2019, 8, 109 2 of 19 in attenuating mitochondrial oxidative damage [6–8]. There has also been research focusing on the application of these mitochondria-targeted antioxidants in the treatment of hearing loss [9–16]. In this systematic review, we will focus on SNHL associated with mitochondrial dysfunction and mitochondria-targeted antioxidant treatments, although a full discussion about the pathophysiology and anti-oxidant therapy in different types of SNHL is beyond the scope. First, we will briefly outline the effect of mitochondrial dysfunction on the disease. After this, we will provide an overview of hearing loss that is suggested to be associated with mitochondrial dysfunction. Finally, we will describe the application of mitochondria-targeted antioxidant treatments developed in recent years for the treatment of hearing loss. 2. Effect of Mitochondrial Dysfunction on Disease Abnormalities in nuclear DNA and mitochondrial DNA (mtDNA) are observed in mitochondria-related diseases. Some of the causative genes of human diseases encode proteins associated with mitochondria. mtDNA contains 37 genes and the abnormalities of mtDNA include point mutations and structural abnormalities, such as deletions and duplications. Furthermore, novel causative nuclear DNA and mtDNA mutations have been discovered using next generation sequencing [17,18]. Mitochondria have various biological roles, such as the production of ATP, generation of ROS, involvement in apoptosis, regulation of intracellular calcium ion concentrations and protection against infection. Abnormalities of mtDNA have various effects on mitochondrial gene expression and lead to the dysregulation of oxidative phosphorylation, generation of ROS and activation of mitochondria-mediated apoptotic pathways. ROS, such as hydrogen peroxide, hydroxyl radicals, singlet oxygen and superoxide anions, are metabolized or scavenged by endogenous antioxidants, such as catalase, superoxide dismutase (Sod) and glutathione, in order to maintain cellular homeostasis [19,20]. However, aging, drug exposure and other factors can alter homeostasis. ROS generation and ROS-induced apoptosis have a large contribution to several diseases, including being a part of SNHL pathologies [3,4,20]. As far as the relationship between mitochondrial dysfunction and ROS is concerned, the mitochondrion is a primary generator of ROS, which are created as byproducts of metabolism [1,2]. ROS causes further damage to mitochondrial components, such as mtDNA, mitochondrial membranes and respiratory chain proteins, as well as nuclear DNA associated with mitochondrial function [5]. Mitochondrial abnormalities cause cell dysfunction and death. In pathological conditions caused by heteroplasmy in mtDNA, it is known that the severity of disease correlates with the level of mtDNA heteroplasmy. The mutation rate varies from cell to cell and cellular dysfunction occurs when the mutation rate exceeds the biochemical threshold [21,22]. Clinical symptoms may appear in tissues and organs where high levels of mutations have accumulated. This property is the basis for the diversity of clinical symptoms seen in mitochondria-related diseases. 3. Overview of Hearing Loss Associated with Mitochondrial Dysfunction 3.1. Hearing Loss Due to Mitochondrial Gene Mutation Mutations in mtDNA are associated with both syndromic and non-syndromic hearing loss. A1555G in mitochondrially encoded 12S rRNA (MT-RNR1) and A3243G in mitochondrially encoded tRNA leucine 1 (UUA/G) (MTTL1) are relatively frequent mtDNA mutations associated with SNHL [23]. With regard to syndromic hearing loss, systemic neuromuscular disorders, such as mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, mitochondrial encephalomyopathy with ragged red fibers and chronic progressive external ophthalmoplegia, frequently have sensorineural hearing loss as one of their findings [24–26]. Mitochondrial mutations are also found in maternally inherited diabetes and deafness [23]. Non-syndromic SNHL associated with mtDNA mutations is generally progressive and symmetric, predominantly involving the high frequency range [27]. For non-syndromic hearing loss, most Antioxidants 2019, 8, 109 3 of 19 of the pathogenic variants have been identified in MT-RNR1 or mitochondrially encoded tRNA serine 1 (MT-TS1) gene [27]. A1555G in MT-RNR1 is the most common non-syndromic mutation. 3.2. ARHL ARHL is a progressive SNHL associated with aging. ARHL is considered to have a multifactorial etiology, including both environmental and hereditary factors. Pathological analyses show that ARHL in humans is generally classified into a loss of sensory HCs, loss of spiral ganglion neurons (SGNs) and atrophy of the stria vascularis [28,29]. Furthermore, most cases of ARHL exhibit mixed pathological changes [28]. It has been suggested that mitochondria are involved in ARHL pathology. The fast-aging senescence accelerated mouse-prone 8 (SAMP8) strain is derived from mice that have been continuously brother–sister mated to select a phenotype of accelerated senescence. This strain was used for gerontological research [30] and showed that premature ARHL is associated with sensory, strial and neural degeneration [31]. The premature ARHL in the SAMP8 strain is thought to be a result of oxidative stress, a change in the level of antioxidant enzymes and a decrease in the activity of complexes I, II and IV, leading to the activation of apoptotic cell death pathways [31]. In the SGNs of the SAMP8 strain, mitochondrial biogenesis decreased in older age when it was examined as the ratio of mtDNA/nuclear DNA and the activity of citrate synthase [31]. A short exposure to H2O2 was used to create a premature senescence model in House Ear Institute-Organ of Corti 1 (HEI-OC1) mouse auditory cells, which exhibited damage to the mitochondrial morphology, a
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